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The Effects of Rare SERPINA1 Variants on Lung Function and Emphysema in SPIROMICS.


ABSTRACT: Rationale: The role of PI (protease inhibitor) type Z heterozygotes and additional rare variant genotypes in the gene encoding alpha-1 antitrypsin, SERPINA1 (serpin peptidase inhibitor, clade A, member 1), in determining chronic obstructive pulmonary disease risk and severity is controversial.Objectives: To comprehensively evaluate the effects of rare SERPINA1 variants on lung function and emphysema phenotypes in subjects with significant tobacco smoke exposure using deep gene resequencing and alpha-1 antitrypsin concentrations.Methods: DNA samples from 1,693 non-Hispanic white individuals, 385 African Americans, and 90 Hispanics with ?20 pack-years smoking were resequenced for the identification of rare variants (allele frequency?SERPINA1.Measurements and Main Results: White PI Z heterozygotes confirmed by sequencing (MZ; n?=?74) had lower post-bronchodilator FEV1 (P?=?0.007), FEV1/FVC (P?=?0.003), and greater computed tomography-based emphysema (P?=?0.02) compared with 1,411 white individuals without PI Z, S, or additional rare variants denoted as VR. PI Z-containing compound heterozygotes (ZS/ZVR; n?=?7) had lower FEV1/FVC (P?=?0.02) and forced expiratory flow, midexpiratory phase (P?=?0.009). Nineteen white heterozygotes for five non-S/Z coding variants associated with lower alpha-1 antitrypsin had greater computed tomography-based emphysema compared with those without rare variants. In African Americans, a 5' untranslated region insertion (rs568223361) was associated with lower alpha-1 antitrypsin and functional small airway disease (P?=?0.007).Conclusions: In this integrative deep sequencing study of SERPINA1 with alpha-1 antitrypsin concentrations in a heavy smoker and chronic obstructive pulmonary disease cohort, we confirmed the effects of PI Z heterozygote and compound heterozygote genotypes. We demonstrate the cumulative effects of multiple SERPINA1 variants on alpha-1 antitrypsin deficiency, lung function, and emphysema, thus significantly increasing the frequency of SERPINA1 variation associated with respiratory disease in at-risk smokers.

SUBMITTER: Ortega VE 

PROVIDER: S-EPMC7047460 | BioStudies | 2020-01-01

SECONDARY ACCESSION(S): rs709932

REPOSITORIES: biostudies

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